Inflammatory diseases, such as rheumatoid arthritis, affect millions of people worldwide. In the United States, rheumatoid arthritis affects more than 1% of the population, at a cost of approximately $15,000 to $20,000 per patient per year. Currently there is no cure for rheumatoid arthritis, which eventually leads to permanent joint damage and functional disability. Conventional treatments involve medications used to mediate the patient's immune system, globally affecting the immune response, to reduce or slow inflammation. For example, corticosteroids are used to reduce disease activity and joint inflammation acutely. However, their long-term use is inappropriate due to major side effects of chronic use including diabetes, cataracts, weight gain, and adrenal suppression. Corticosteroids are often used to control symptoms and flares of joint inflammation until disease-modifying anti-rheumatic drugs (also termed DMARDs) reach their full effectiveness, which can take up to 6 months.
Disease-modifying anti-rheumatic drugs can be divided into two general categories based on how they work: oral DMARDs and biological DMARDs. Oral DMARDs are taken by mouth. They interfere with the making or working of immune cells that cause joint inflammation. Biological DMARDs are given by injection (infusion). They act in several different ways to affect how immune cells work. DMARDs decrease joint inflammation and damage. Because they work throughout the body to fight rheumatoid arthritis, they are also associated with serious side effects, including life-threatening infections, hematologic issues, kidney and liver damage, severe immunosuppression and death, as well as long-term effects such as increased risk of cancer. Intense blood work is usually required to monitor the drug's effect. DMARDs are usually started within 3 months of diagnosis and are used to control the progression of rheumatoid arthritis and to try to prevent joint deterioration and disability.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, or naproxen are used to control pain and may help reduce inflammation. They do not control the disease or stop it from progressing. NSAIDs may be combined with DMARDs.
None of the drug-based therapies currently in use are successful in halting the progression of inflammatory disease. Presently, the only option at end stage disease is total joint replacement. Accordingly, novel therapies for the treatment of inflammatory diseases, slowing or stopping their advance, and reducing the incidence and need for joint replacement surgeries, are desirable. Such therapies will preferably have a more localized action, and will not directly affect immune-system function or pathways, and thus produce unwanted side effects.
During inflammation, serum exudates enter tissues, bathing the macromolecular hyaluronan (also termed hyaluronate, hyaluronic acid, or HA) found in most tissue extracellular matrices (ECM) with the serum-derived proteoglycan inter-α-inhibitor (IαI). Heavy chains (HC) of IαI are transferred from IαI to HA by the enzyme tumor necrosis factor stimulated gene-6 (TSG-6), a protein expressed at sites of inflammation, causing a pathological transformation to the HA matrix. This pathological transformation functions as a specific ligand for inflammatory cells. The formation of HC-HA complexes transform normally benign HA matrix molecules into pathological HA that includes specific ligands for inflammatory cell receptors contributing to inflammatory disease processes through binding and activation of inflammatory cells. Strategies that would allow for the in vivo manipulation of HC transfer both to and from HA in inflamed tissues may provide a therapy for treatment of a wide variety of inflammatory diseases.